Autism is a progressive neurodevelopment disorder defined primarily by abnormal behavioral features including deficits in social interactions, language dysfunction, and stereotypic behaviors, many of which reflect defects in higher-order (executive) functions. Numerous patients with autism show a relative enlargement of brain size, with anterior structures such as the frontal cortex most affected; also within the cortex, defects in minicolumn formation have been described. Linkage between autism and GABRB3, the dominant beta subunit of GABAA-receptors in differentiating cortical neurons, is enhanced using subgroups of patients exhibiting higher-level repetitive behaviors. By micro array, qRT-PCR and Western blot analysis, GABRB3 expression is decreased in brain samples from some individuals with autism spectrum disorders. However, GABAA-receptor mutations have not been identified in patients with autism. We suggest that the inability to identify non-synonymous mutations in autism may be because such mutations lead to a severe, early phenotype, as observed in Gabrb3-knockout mice. In contrast, heterozygous animals have only subtle defects, as a consequence of compensatory up regulation of Gabrb3 expression to 70-80% wild-type levels at birth. We propose that low GABRB3 expression during development may more accurately reflect phenotypic severities observed in autism. Furthermore, GABRB3 exhibits developmentally regulated, alternative promotor usage as well. As alteration of total or isoform-specific expression of many genes, including other GABAA-receptor subunits has considerable functional and phenotypic effect, we hypothesize that aberrant GABRB3 expression, including alterations in variant-specific or total expression, rather than mutation, underlies chromosome 15-associated autism. To further characterize the role of Gabrb3 transcription variation in development, and its contribution to the autism phenotype, we propose to: 1) Generate RNAi-mediated knock-down Gabrb3 mice; and 2) Characterize the phenotypic consequences of decreased total and variant-specific Gabrb3 expression. These analyses will define the role of variation of the autism candidate gene GABRB3 in neurodevelopment and in specific features of autism such as perseveration and social intelligence, which will lead to greater insight into the etiology and treatment of autism and autism spectrum disorders. [unreadable] [unreadable] [unreadable]